Bone fragility fractures occur due to diminished skeletal mechanical integrity associated with reduced bone mass and/or material quality of bone tissue. Diseases caused by single gene mutations, such as the various forms of Osteogenesis Imperfecta and hypophosphatemic rickets, show that the amount, shape, and material quality of bones determine their overall resistance to fracture. This is also true in subtle and more complex genetic diseases of bone such as osteoporosis; however, the underlying genetic factors controlling strength are less defined. The genetics of whole bone strength have been examined in a number of ways, but largely from the point of view of restricting examination to the genetic regulation of bone size and shape. The genetic regulation of bone matrix composition and quality as a material remain less studied. The overarching goal of this application is to find the genes that control bone tissue mechanical integrity, with a focus on the genetic regulation of bone composition and quality. The secondary goal of this application is to determine the contribution of genetic factors to the maintenance of bone quality with aging. It is well understood that the incidence of fragility fracture increases with age, and that the quality of bone tissue decreases with age, but the involvement of genetics in either slowing or speeding this decline is largely undefined. In Aim 1 of this application, we will use the Heterogeneous Stock Rat (HS Rat) to identify genes and genetic loci that regulate bone matrix composition and mechanical integrity (collectively defining bone quality), as well as their integration with bone size and shape to account for the overall strength of a bone. The HS is an outbred rat population that was initially created by interbreeding 8 inbred rat strains. The population was started in 1984 and since that time over 75 generations of breeding have occurred, accumulating a high density of genetic recombinations which provide for finer genetic mapping. Previous studies have demonstrated that bone size and shape vary in the HS progenitor population, and that long bone strength is genetically regulated in the HS Rat population. In combination with the aforementioned genetic structure of the HS Rat, these preliminary data indicate that this population is ideal for genetic mapping of bone composition and quality. In Aim 2, we will use inbred rat strains to ascertain how bone matrix composition and mechanical integrity change with age, and how genetic background contributes to these changes. These studies will yield novel genetic loci and genes that contribute to the genetic regulation of bone strength, and will help to elucidate the genetic role of age-related decline in bone quality.